Adolescence is a critical period during which alcohol drinking increases the risk of lifetime alcohol use disorders (AUDs). However, the neurobiological mechanisms that mediate this increased risk have not been fully identified. To break new ground in our understanding of adolescent vulnerability to AUDs, we propose to conduct a high-throughput screen of the prefrontal cortex (PFC) proteome in mice to identify protein interaction networks that are modified by ethanol in the adolescent and adult mouse brain. These discovery-based experiments will identify novel alcohol-sensitive protein networks in adolescent PFC. Preliminary proteomic findings identified the cannabinoid receptor interacting protein 1a (CRIP1a) as a developmentally regulated ethanol-sensitive protein in the adolescent PFC. Evidence suggests that the endocannabinoid system functionally regulates alcohol drinking in rodents, and significant changes in expression of the cannabinoid receptors occur in the developing brain. Therefore, experiments in this application will also establish a functional role for CRIP1a in adolescent and adult alcohol drinking and determine whether CRIP1a expression mediates the long-term consequences of adolescent alcohol drinking. To determine whether CRIP1a mediates the long-term risk for abuse following adolescent alcohol drinking, we will use viral vector-mediated overexpression of CRIP1a in the adolescent and adult PFC to drive long-term increases in CRIP1a expression and measure operant self-administration of alcohol during adulthood in both age groups. As this manipulation will oppose the effect of ethanol in the adolescent PFC, we expect that it will be protective against enhanced reinforcing effects of alcohol in the adolescent but not adult treatment groups. Together, these experiments will identify novel alcohol sensitive protein-networks in the adolescent PFC and determine if a specific node in these networks, CRIP1a, mediates risk for escalated alcohol self-administration during adulthood after adolescent alcohol exposure.